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Comparison 1 Antifungals versus placebo or no treatment, Outcome 1 Death.
Figures and Tables -
Analysis 1.1

Comparison 1 Antifungals versus placebo or no treatment, Outcome 1 Death.

Comparison 1 Antifungals versus placebo or no treatment, Outcome 2 Death related to fungal infection.
Figures and Tables -
Analysis 1.2

Comparison 1 Antifungals versus placebo or no treatment, Outcome 2 Death related to fungal infection.

Comparison 1 Antifungals versus placebo or no treatment, Outcome 3 Invasive infections.
Figures and Tables -
Analysis 1.3

Comparison 1 Antifungals versus placebo or no treatment, Outcome 3 Invasive infections.

Comparison 1 Antifungals versus placebo or no treatment, Outcome 4 Colonisation.
Figures and Tables -
Analysis 1.4

Comparison 1 Antifungals versus placebo or no treatment, Outcome 4 Colonisation.

Comparison 1 Antifungals versus placebo or no treatment, Outcome 5 Use of escape drug.
Figures and Tables -
Analysis 1.5

Comparison 1 Antifungals versus placebo or no treatment, Outcome 5 Use of escape drug.

Table 1. Harms

Trial

Trial drug

Number of patients

Harms

EORTC 1989

amphotericin B

80 versus 77

Treatment discontinuations: 6 pts on trial drug (infusion‐related toxicity, allergic reactions); Nephrotoxicity: 8 versus 3, none required dialysis and renal function restored later; Hypokalaemia: 33 versus 16

Goldstone 1994

amphotericin B

64 versus 69

Treatment discontinuations: 4 on trial drug (chills, rigour, hypotension, rash and bronchospasm); Elevated liver function tests: 26 versus 32; Nephrotoxicity: 1 on trial drug that did not require withdrawal of therapy

Kelsey 1999

amphotericin B

74 versus 87

Treatment discontinuations: 5 on trial drug, 1 on placebo because of immediate reactions; Nephrotoxicity: 9 versus 6; Hypokalaemia: 1 versus 0; Clinical adverse events were very similar in the two groups

Penack 2006.

amphotericin B

75 versus 57

Treatment discontinuations: 2 (1 skin rash, 1 chills) versus 0; Other harms: "no differences in ... liver function tests, renal function parameters and hypokalaemia"

Perfect 1992

amphotericin B

91 versus 91

More infusion‐related harms on active drug, but no data provided; No significant differences in renal function, hepatic enzymes or electrolytes (no data provided)

Pizzo 1982

amphotericin B

18 versus 16

Treatment discontinuations: none; Rash: 2 versus 1; Azotaemia: 1 versus 0; liver enzyme elevations: 2 versus 3; Electrolyte abnormalities: 18 versus 16

Riley 1994

amphotericin B

17 versus 18

Treatment discontinuations: none; Renal function: no difference (P value 0.82 for blood urea, P value 0.63 for creatinine); Potassium supplements: no difference; Infusion reactions: none

Suda 1980

amphotericin B

39 versus 31

Article is in Japanese

Tollemar 1993

amphotericin B

42 versus 42

Treatment discontinuations: 4 versus 0 for infusion reactions; Potassium supplementation: no difference; Renal function: no useful data, but only small changes reported, compared to normal ranges

Fukuda 1994

fluconazole

37 versus 26

Article is in Japanese

Goodman 1992

fluconazole

179 versus 177

Treatment discontinuations: 1 on trial drug, 2 on placebo for clinical side effects, and 17 versus 11 for elevated liver function tests; in 7 versus 3, hepatic dysfunction contributed to death; Graft‐versus‐host disease or organ failure: 44 versus 24 deaths; Nausea: 13 versus 9; Skin rash: 9 versus 9; Eosinophilia in 6 versus 0

Kern 1998

fluconazole

36 versus 32

Bacteriaemia: 15 versus 7; Other harms similar: 5 versus 6 elevations in transaminases, 19 versus 17 nausea or vomiting, 3 versus 0 allergy

Rotstein 1999

fluconazole

141 versus 133

Treatment discontinuations: none reported; Elevated liver enzymes: 17 versus 19; Rash: 51 versus 59; Nausea: 106 versus 95; Vomiting: 68 versus 85

Schaffner 1995

fluconazole

76 versus 76 episodes

Treatment discontinuations: none reported; No data on harms ("no significant differences were found")

Slavin 1995

fluconazole

152 versus 148

Treatment discontinuations: 32 versus 31 for abnormal liver function; Graft‐versus‐host disease: 102 versus 85; Nausea: 33 versus 22; Seizures: 8 versus 9; Liver enzymes: no differences

Winston 1993

fluconazole

124 versus 133

Treatment discontinuations: none reported; Elevated liver enzymes: 25 versus 14; Nausea and vomiting: 9 versus 5; Rash: 13 versus 7; Other harms were similarly distributed

Yamac 1995

fluconazole

41 versus 29

Treatment discontinuations: none reported; Other harms: no data

Acuna 1981

ketoconazole

28 versus 24

No data

Benhamou 1991

ketoconazole

63 versus 62

Treatment discontinuations: 38 versus 14 (among them 2 patients with veno‐occlusive disease, 1 hepatitis, 3 skin rash in active group; none in placebo group); Severe gastrointestinal intolerance: 4 versus 7; Three‐fold greater values than normal for transaminases: 13 versus 8

Brincker 1983

ketoconazole

19 versus 19

One patient on trial drug stopped treatment because of universal exanthema

Estey 1984

ketoconazole

77 versus 73

Bacterial infections: 33 versus 24

Hansen 1987

ketoconazole

27 versus 29

Treatment discontinuations: 2 on trial drug (1 skin rash and 1 elevated liver function tests); Bacterial infections: 20% versus 15% of neutropenic episodes

Hughes 1983

ketoconazole

42 versus 22

Treatment discontinuations:1 on trial drug (nausea and anorexia); Other harms: 2 nausea and anorexia, 1 abdominal pain, 1 transient rash, all on trial drug

Palmblad 1992

ketoconazole

55 versus 61

Treatment discontinuations: 2 (elevated transaminases) versus 6 (1 elevated transaminases, 5 exanthema); Bacteriaemias: 37 versus 21

Siegel 1982a

ketoconazole

12 versus 13

No data

Brincker 1978

miconazole

15 versus 15

None ascribable to trial drug

Wingard 1987

miconazole

97 versus 111

Treatment discontinuations: 1 (pruritis and flushing) versus 2 (1 rash, 1 nausea); Severe hypotension: 2 on trial drug

Caselli 1990

itraconazole, amphotericin B, ketoconazole

30 versus 10

No data

Kaptan 2003

itraconazole

31 versus 24

Treatment discontinuations: 2 on trial drug (cardiac arrhytmia and gastric irritation); "there was a clinical impression that hypokalaemia occurred at a greater rate in patients with itraconazole"

Menichetti 1999

itraconazole

201 versus 204

Treatment discontinuations: 37 versus 27; Bacteriaemia: 47 versus 31; Elevated transaminases: 5 versus 3

Nucci 2000

itraconazole

104 versus 106

Treatment discontinuations: 3 versus 4; Skin rash: 3 versus 1; Elevated liver enzymes: 3 versus 4; Nausea: 2 on placebo

Vreugdenhil 1993

itraconazole

49 versus 49

Treatment discontinuations: 1 (nausea) versus 1 (liver function deterioration); Liver function deterioration: 28 versus 22 episodes; Renal function deterioration: 4 versus 2 episodes

Figures and Tables -
Table 1. Harms
Comparison 1. Antifungals versus placebo or no treatment

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

26

3902

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.81, 1.09]

1.1 Amphotericin

9

988

Risk Ratio (M‐H, Fixed, 95% CI)

0.69 [0.50, 0.96]

1.2 Fluconazole

7

1470

Risk Ratio (M‐H, Fixed, 95% CI)

1.04 [0.84, 1.30]

1.3 Ketoconazole

4

429

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.63, 1.49]

1.4 Miconazole

2

238

Risk Ratio (M‐H, Fixed, 95% CI)

1.16 [0.71, 1.87]

1.5 Itraconazole

4

777

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.63, 1.40]

2 Death related to fungal infection Show forest plot

23

3490

Risk Ratio (M‐H, Fixed, 95% CI)

0.52 [0.38, 0.71]

2.1 Amphotericin

9

988

Risk Ratio (M‐H, Fixed, 95% CI)

0.45 [0.26, 0.76]

2.2 Fluconazole

6

1213

Risk Ratio (M‐H, Fixed, 95% CI)

0.42 [0.24, 0.73]

2.3 Ketoconazole

3

304

Risk Ratio (M‐H, Fixed, 95% CI)

1.49 [0.55, 4.04]

2.4 Miconazole

1

208

Risk Ratio (M‐H, Fixed, 95% CI)

0.13 [0.01, 2.33]

2.5 Itraconazole

4

777

Risk Ratio (M‐H, Fixed, 95% CI)

0.70 [0.31, 1.56]

3 Invasive infections Show forest plot

30

4044

Risk Ratio (M‐H, Fixed, 95% CI)

0.50 [0.39, 0.64]

3.1 Amphotericin

8

855

Risk Ratio (M‐H, Fixed, 95% CI)

0.41 [0.24, 0.73]

3.2 Fluconazole

8

1539

Risk Ratio (M‐H, Fixed, 95% CI)

0.39 [0.27, 0.57]

3.3 Ketoconazole

7

562

Risk Ratio (M‐H, Fixed, 95% CI)

1.32 [0.68, 2.54]

3.4 Miconazole

2

238

Risk Ratio (M‐H, Fixed, 95% CI)

0.52 [0.20, 1.31]

3.5 Itraconazole

4

810

Risk Ratio (M‐H, Fixed, 95% CI)

0.53 [0.29, 0.97]

3.6 Itraconazole/ketoconazole/amphotericin

1

40

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Colonisation Show forest plot

22

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 Amphotericin

3

378

Risk Ratio (M‐H, Random, 95% CI)

0.51 [0.33, 0.77]

4.2 Fluconazole

6

1393

Risk Ratio (M‐H, Random, 95% CI)

0.55 [0.33, 0.90]

4.3 Ketoconazole

8

626

Risk Ratio (M‐H, Random, 95% CI)

0.67 [0.51, 0.87]

4.4 Miconazole

2

238

Risk Ratio (M‐H, Random, 95% CI)

0.92 [0.37, 2.24]

4.5 Itraconazole

2

503

Risk Ratio (M‐H, Random, 95% CI)

0.91 [0.57, 1.45]

4.6 Itraconazole/ketoconazole/amphotericin

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.57 [0.31, 1.04]

5 Use of escape drug Show forest plot

24

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5.1 Amphotericin

6

636

Risk Ratio (M‐H, Random, 95% CI)

0.60 [0.35, 1.03]

5.2 Fluconazole

7

1469

Risk Ratio (M‐H, Random, 95% CI)

0.88 [0.76, 1.02]

5.3 Ketoconazole

6

412

Risk Ratio (M‐H, Random, 95% CI)

0.92 [0.58, 1.44]

5.4 Miconazole

2

238

Risk Ratio (M‐H, Random, 95% CI)

1.17 [0.94, 1.46]

5.5 Itraconazole

3

712

Risk Ratio (M‐H, Random, 95% CI)

0.74 [0.57, 0.95]

Figures and Tables -
Comparison 1. Antifungals versus placebo or no treatment